Inbred strains of mice vary in their susceptibility to the agent of murine typhoid. Salmonella typhimurium. Two autosomal genes (Ity and Lps d) and one X-linked gene (xid) govern this differential sensitivity. Mice succumb to parenteral infection with fewer than 20 organisms if they express either xid, Lps d, or the Ity susceptibility allele (Ity s). By contrast, the 50% lethal dose of S. typhimurium for mice with the Ity resistance allele (Ity r) is greater than or equal to 1000. Current evidence indicates that Ity r mice can restrict early net growth of salmonellae in their splenic and hepatic macrophages whereas Ity s and Lps d mice are unable to contain the bacterial population. The xid allele appears to prevent formation of protective antibody. The goal of this project is to define further the mechanisms whereby these genes confer susceptibility or resistance. First, the mechanisms of Ity r-restricted bacterial multiplication will be investigated by several approaches. Both in vivo and in vitro tehhniques will be used to compare the phagocytic, bacteriostatic, and bactericidal capacity of Ity r, Its s, and Lps d macrophages. The generation and mobilization of macrophages and their precursors will also be examined in S. typhimurium-infected mice of these genotypes. In addition, the importance of various macrophage functions and the role of T cells in the expression of salmonella resistance will be determined by analysis of the early growth of salmonellae in macrophage-defective and nude mice, respectively. Second, since passive transfer of immune serum increases the resistance of xid mice, the nature of the xid anti-salmonella antibody defect will be determined by an assessment of the protective capacity of immune serum either (a) adsorbed with selected bacterial mutants; (b) prepared against specific bacterial components; or (c) fractionated by affinity chromatography. These studies will clarify the mechanisms of genetically-conferred resistance of mice to S. typhimurium. This investigation can also provide a basis for future studies of immunity to typhoid fever in man because murine typhoid is an excellent experimental model for the pathogenesis of the human disease.